Daniel Delduca
Research Mentor(s): Yuji Mishina
Mentor Department: Biological and Material Sciences
Authors: Daniel Delduca, Sher Khehra, Yuji Mishina
Session: Session 5 (2:00pm – 2:50pm)
Presentation Type: Poster 22
Abstract
Ellis-van Creveld (EVC) syndrome is a genetic disorder characterized by chondrodysplastic dwarfism showing defects in skeletal, oral, and respiratory systems, which could lead to death in infancy (Louie et al, 2020). Tracheal cartilage defects may result in collapse of the trachea, a condition called laryngotracheobronchomalacia (Louie et al, 2020). One identified cause of EVC syndrome is a mutation in the Evc2 gene (Zhang et al, 2015), so we first generated an Evc2 mutant mouse line (hereafter, Evc2 mutant). Evc2 mutants displayed skeletal and tracheal abnormalities comparable to EVC patients such as shorter long bones. These tracheal defects often result in death shortly after birth. To understand the mechanisms behind the Evc2 mutant phenotype, we examined early stages of mutant embryos to identify significant reduction of Bone morphogenetic protein (BMP) signaling in Evc2 mutant embryos, which is critical for skeletogenesis. We hypothesized that augmenting BMP signaling would rescue the Evc2 mutant phenotype. To test this hypothesis, we administered FK506 (FK), an upregulator of BMP signaling to pregnant mothers. Embryos were treated with FK from embryonic E9.75 until -E12.5 or from E10.75 until -E13.5, and dissected two days after birth. We found that FK-treated mutants showed partially rescued trachea in association with improved survivability, compared to Evc2 given a control treatment. We did not see this improvement through the E10.75-E13.5 treatment regimen. We next investigated if a treatment starting one day earlier from E8.75 would further improve Evc2 mutant survivability. The findings were similar to the E9.75-E12.5 treatment schedule, indicating a critical time window for augmentation of BMP signaling is at E9.75, but not E8.75 or E10.75. Neither schedule rescued the long bone phenotype, however, suggesting that function of EVC2 in tracheal cartilage is different from that in cartilage primordia for long bones.
